Title: Retrospective Analysis of Clinical Progression Over 6 Months in Three Clinical Trials of
Edaravone in Amyotrophic Lateral Sclerosis (ALS), Using the King’s ALS Clinical Staging System 1
1
Additional authors (in order): Rebecca K. Bornheimer, B.A., Ellen M. Dukes, R.N., Ph.D., 2
2
3
Wendy Agnese, Pharm.D., Charlotte Merrill, Ph.D., M.B.A., Pingping Ni, Ph.D., Marc Rivière, M.D.,4 Gerry Oster, PhD1 Institution name, city, state, country of additional authors:
(1) Policy Analysis Inc, Brookline, MA, USA (2) Mitsubishi Tanabe Pharma America, Inc., Jersey City, NJ, USA (3) Mitsubishi Tanabe Pharma Europe, Ltd., London, UK (4) TVM Capital Life Science Venture Capital, Montreal, Quebec, Canada
Introduction: The King’s ALS Clinical Staging (“King’s”) System, first described in 2012, measures extent of anatomical involvement (upper limb, lower limb, bulbar, need for tracheostomy/gastrostomy) in patients with ALS; it has been suggested as a possible primary outcome in randomized trials. In a Phase III clinical trial (Protocol MCI186-J19), edaravone was found to delay functional decline over 24 weeks as assessed by the Revised ALS Functional Rating Scale (ALSFRS-R) total score. Since it was unavailable when J19 began, we retrospectively examined the impact of edaravone on clinical progression in this Phase III trial, as well as well as two prior Phase II trials (J16 and J18), using the King’s System. Hypothesis: To explore the potential utility of the King’s ALS Clinical Staging System as a measure of clinical progression in ALS clinical trials. Methodology: In all 3 trials, patients were randomized (1:1) to six 28-day cycles (C) of edaravone 60 mg/d or placebo (C1: 14 days; C2-C6: 10 days each). At study entry, ALS duration was ≤2 years in J19, and ≤3 years in J16 and J18; forced vital capacity (FVC) was ≥80% in J19, ≥70% in J16, and ≥60% in J18. Using data from these trials, we retrospectively mapped each patient’s ALSFRS-R item scores to King’s using a published algorithm, and examined the percentage of edaravone and placebo patients who experienced any decline in clinical stage between baseline and end of study (24 weeks) in J19 (n=137), and in all 3 trials combined (n=367), respectively. Results: Approximately 80% of patients were King’s Stage 1 or 2 at entry into the trials. In J19, after 6 cycles of study therapy, 42.0% (95% confidence interval [CI]: 30.4%, 53.6%) of edaravone patients had declined ≥1 King’s Stage vs 55.9% (95%CI: 44.1%, 67.6%) among those receiving placebo. In pooled analyses across the 3 trials, corresponding estimates were 38.3% (95%CI: 31.1%, 45.4%) and 51.6% (95%CI: 44.6% vs 58.7%). Conclusion: Our retrospective analysis suggests that the King’s ALS Clinical Staging System may be of value in evaluating the potential benefits of new therapeutic agents.
